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A framework for remission in SLE: consensus findings from a large international
task force on definitions of remission in SLE (DORIS)
The Definition of Remission in SLE (DORIS) task force
Corresponding author:
Ronald van Vollenhoven
Amsterdam Rheumatology and immunology Center ARC
Amsterdam, Netherlands
Authors:
Ronald van Vollenhoven1,2, Alexandre Voskuijl2, George Bertsias3, Cynthia Aranow4, Martin
Aringer5, Laurent Arnaud1, Anca Askanase6, Petra Balážová7, Eloisa Bonfa8, Hendrika Bootsma9,
Dimitrios T Boumpas10, Ian N Bruce11, Ricard Cervera12, Ann Clarke13, Cindy Coney14, Nathalie
Costedoat-Chalumeau15, László Czirják16, Ronald Derksen17, Andrea Doria18, Thomas Dörner19,
Rebecca Fischer-Betz20, Ruth Fritsch-Stork17, Caroline Gordon21, Winfried Graninger22, Noémi
Györi1, Frédéric Houssiau23, David Isenberg24, Soren Jacobsen25, David Jayne26, Annegret Kuhn27,
Veronique Le Guern15, Kirsten Lerstrøm28, Roger A. Levy29, Francinne Machado-Ribeiro29, Xavier
Mariette30, Jamil Missaykeh31, Eric Morand32, Marta Mosca33, Murat Inanc34, Sandra Navarra35,
Irmgard Neumann36, Marzena Olesinska37, Michelle Petri38, Anisur Rahman24, Ole Petter Rekvig39,
Jozef Rovensky40, Yehuda Shoenfeld41, Josef S. Smolen42, Angela Tincani43, Murray Urowitz44,
Bernadette van Leeuw28, Carlos Vasconcelos45, Victoria P. Werth46, Anne Voss47, Helena
Zakharova48, Asad Zoma49, Matthias Schneider20, Michael Ward50.
Affiliations
1Karolinska Institutet, Department of Medicine, Unit for Clinical Therapy Research, Inflammatory
Diseases (ClinTRID), D1:00 Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden.
2 Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam,
The Netherlands
3 Rheumatology, Clinical Immunology and Allergy, University of Crete School of Medicine, 2209
Iraklion, Greece
4 Feinstein Institute for Medical Research, Manhasset, New York, USA
5 Department of Medicine III, University Medical Center TU Dresden, Dresden, Germany
2
6 New York University, New York, USA.
7 LPRe SR - Klub Motýlik, Bratislava, Slovakia.
8 Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, Brazil.
9 Department of Rheumatology and Clinical Immunology, University of Groningen, University
Medical Center Groningen, Groningen, The Netherlands.
10 Department of Medicine and Joint Academic Rheumatology Program Medical School, National
and Kapodestrian University of Athens, Greece.
11 NIHR Manchester Biomedical Research Unit, The University of Manchester and Central
Manchester Foundation Trust, Manchester, UK.
12 Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Catalonia, Spain.
13 Division of Rheumatology The Arthritis Society Chair in Rheumatic Diseases Cumming School of
Medicine University of Calgary, Calgary, Alberta, Canada
14 Lupus Foundation of America, 2000 L Street, NW, Suite 410, Washington, DC, 20036, USA
15 Université Paris-Decartes, Paris, France; AP-HP, Hôpital Cochin, service de médecine interne,
centre de reference maladies auto-immunes et systémiques rares, 27 rue du Faubourg Saint-Jacques,
75014 Paris, France
16 Institute of Bioanalysis, Institute of Family Medicine, Department of Rheumatology and
Immunology, University of Pécs, Pécs and Third Department of Internal Medicine, Semmelweis
University, Budapest, Hungary.
17 University Medical Center, Dpt. Rheumatology and Clinical Immunology, Heidelberglaan 100,
3584CX Utrecht, The Netherlands.
18 Rheumatology Unit, Department of Medicine, University of Padova, Italy.
19 Department Medicine/Rheumatology and Clinical Immunology, Charite Universitätsmedizin
Berlin, Chariteplatz 01, 10117 Berlin, Germany.
20 Policlinic of Rheumatology, Hiller Research Unit, University Clinic Duesseldorf, Heinrich-Heine-
University, Germany.
21 Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and
Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
22 Division of Rheumatology, Medical University of Graz, Graz, Austria.
23 Service de Rhumatologie, Cliniques universitaires Saint-Luc, Pôle de pathologies rhumatismales
inflammatoires et systémiques, Institut de Recherche Expérimentale et Clinique, Université
catholique de Louvain, Bruxelles, Belgium.
24 The Centre for Rheumatology, Department of Medicine, University College London, UK
3
25 Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases,
Rigshospitalet, DK-2100 Copenhagen, Denmark
26 Department of Medicine, University of Cambridge, Cambridge, UK
27 Interdisciplinary Center for Clinical Trials (IZKS), University Medical Center Mainz, Mainz,
Germany.
28 LUPUS EUROPE, co-opted trustee for research, St James House 27-43 Eastern Road Romford,
Essex RM1 3NH, UK
29 Rheumatology Department at Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
30 Université Paris-Sud; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-sud;
INSERM U1184, Le Kremlin Bicêtre, France
31 Bone Densitometry Unit, Monla Hospital, Tripoli, Lebanon.
32 Monash University Faculty of Medicine, Nursing & Health Sciences, Level 3, Block E,
Monash Medical Centre, 246 Clayton Road, Clayton VIC 3168, Australia.
33 Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy
34 Istanbul University, Istanbul Medical Faculty, Department of Internal Medicine, Division of
Rheumatology, Capa, Istanbul, Turkey.
35 University of Santo Tomas, Manila, Philippines.
36 Vasculitis.at, Vienna, Austria
37 Department of Connective Tissues Diseases, National Institute of Geriatrics, Rheumatology and
Rehabilitation, Warsaw, Poland.
38 Johns Hopkins University School of Medicine, Baltimore, USA
39 RNA and Molecular Pathology Research Group, Institute of Medical Biology, Health Science
Faculty, University of Tromsø, Norway
40 National Institute for Rheumatic Diseases, 92101 Piešťany, Slovak Republic.
41 Zabludowicz Center for Autoimmune Diseases,Sheba Medical Center (Affiliated to Tel-Aviv
University) Tel-Hashomer 5265601, Israel
42 Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, and 2nd
Department of Medicine, Hietzing Hospital, Vienna, Austria.
43 Dipartimento di Scienze Cliniche e Sperimentali, Università degli Studi di Brescia, U.O.
Reumatologia e Immunolgia Clinica, Spedali Civili di Brescia, Brescia, Italy
44 Centre for Prognosis Studies in the Rheumatic Diseases, Senior Scientist Krembil Research
Institute, Professor Medicine, University of Toronto, Toronto Western Hospital EW 1-409, Toronto,
ON M5T 2S8, Canada
4
45 Unidade de Imunologia Clínica, Hospital Santo António, Centro Hospitalar do Porto, UMIB,
Instituto de Ciencias Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
46 Corporal Michael J. Crescenz VA Medical Center (Philadelphia), Philadelphia, Philadelphia, USA.
Department of Dermatology, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, USA
47 Department of Rheumatology, Odense University Hospital, University of Southern Denmark,
Denmark.
48 Nephrology Unit, City Clinical Hospital n.a. S.P. Botkin, Moscow, Russia.
49 Lanarkshire Centre for Rheumatology, Hairmyres Hospital, East Kilbride G75 8RG, Scotland, UK
50 National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of
Health, Bethesda, USA
Keywords: systemic lupus erythematosus, systematic review, consensus, remission, disease activity
Word count: 3679
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Abstract
Objectives. Treat-to-target recommendations have identified ‘remission’ as a target in systemic
lupus erythematosus (SLE) but recognize that there is no universally accepted definition for this.
Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE.
Methods. An international task force of sixty specialists and patient representatives participated in
preparatory exercises, a face-to-face meeting, and follow-up electronic voting. The level for
agreement was set at 90%.
Results.
The task force agreed on eight key statements regarding remission in SLE and three principles to
guide the further development of remission definitions:
1. Definitions of remission will be worded as follows: Remission in SLE is a durable state
characterized by …………………. (reference to symptoms, signs, routine labs).
2. For defining remission a validated index must be used, e.g., clinical-SLEDAI = 0,
BILAG2004 D/E only, clinical ECLAM =0; with routine laboratory assessments included,
and supplemented with Physician Global Assessment.
3. Distinction is made between remission off and on therapy: Remission-off-therapy requires the
patient to be on no other treatment for SLE than maintenance antimalarials; and Remission-
on-therapy allows patients to be on stable maintenance antimalarials, low-dose
corticosteroids (prednisone <5 mg/d), maintenance immunosuppressives and/or maintenance
biologics.
The task force also agreed that the most appropriate outcomes (dependent variables) for testing the
prognostic value (construct validity) of potential remission definitions are: Death, Damage, Flares,
and measures of Health-related quality of life.
Conclusion. The work of this international task force provides a framework for testing different
definitions of remission against longer-term outcomes.
6
Introduction
Outcomes in systemic lupus erythematosus (SLE) have improved considerably over the past decades.
For the most widely studied specific organ involvement in SLE, lupus nephritis, results from clinical
trial follow-up studies demonstrate that the long-term renal survival in this condition has now
improved to greater than 90%.[1] However, not all outcomes in SLE show the same favorable trends.
Most notably the overall health-related quality of life (HR-QoL) for patients with SLE remains
reduced.[2]. This and other considerations prompted the initiation of the Treat-to-Target for SLE
(T2T/SLE), initiative which over the past several years established an international consensus on the
approach to the therapy of SLE based on 1) identifying an appropriate target for each patient; 2)
initiating treatment steps to try to achieve this target; 3) assessing the target; and 4) adjusting the
therapeutic approach, if necessary. These elaborations led to the T2T/SLE recommendations
published in 2014.[3] One of the most significant targets in SLE was identified as “remission of
systemic symptoms and organ manifestations”. However, it was recognized by the panel that no
generally accepted definition of remission in SLE exists today. Such a definition could be important
for basic, clinical and epidemiological studies and clinical trials in lupus, but also for clinical
practice. The literature on this topic demonstrates that many clinical trials and observational studies
have used a large number of different ad hoc definitions of remission; many of these were reviewed
in a recent study.[4] Consequently, the T2T/SLE panel identified the definition of remission as a
research priority for SLE. In response, an initiative was undertaken in order to achieve consensus in a
large multiparty international task force on potential definitions of remission in SLE (DORIS).
Methods
An international task force consisting of rheumatologists, nephrologists, dermatologists, clinical
immunologists and patient representatives, totaling 60 individuals, was convened. In March 2014, a
7
preliminary meeting was held by a steering committee consisting of 15 of these representatives. The
steering committee identified four domains critical to further development of remission definitions;
ten preliminary statements regarding remission that were felt to be uncontroversial; key
controversies; and a set of proposed topics for further discussion. During the following 4-month
period, the ten preliminary statements were presented to the full task force electronically, deliberated
upon by email, and then subjected to formal electronic voting. High-level agreement was readily
achieved for eight of these, whereas two were placed on the agenda for the subsequent consensus
conference. Moreover, an additional number of key topics were identified during these deliberations
that were to be dealt with more thoroughly at the face-to-face meeting.
In August 2014, a consensus conference took place where a large majority of the full task force was
present. The explicit goal of this consensus conference was to establish guiding principles for
working towards a definition of remission in SLE and to formulate proposed definitions that would
be amenable to scientific testing. During this meeting, formal votes were taken on a range of points.
The level for agreement was set at >90%.
The procedure was informed by the results of the systematic literature review that was carried out in
the context of the ‘Treat-to-target in SLE’ project [3] and was modified and updated in September
2015. We focused on two of the twelve original topics of interest that were more relevant to the
present study, namely topic #2 (“Have any definitions for low disease activity and remission, -both
global and organ-specific-, been validated as surrogates of therapeutic success against damage
accrual, mortality, and QoL in SLE?”) and topic #5 (“Is sustained reduction of disease activity or
prevention of flares, -both general and organ-specific-, an achievable goal in SLE?”).[3] The
literature search was repeated in September 2015 by author GB to include more recently published
literature. The PubMed database was searched using index terms and all English-language human
studies were evaluated based on the title, abstract and/or full-text. For the purpose of the present
8
study, we report on the systematic literature review results relevant to remission only, which were
published since the year 1990 and included ≥70 SLE patients.
Results
Domains considered critical for defining remission in SLE. Four domains critical for defining
remission in SLE were identified: clinical disease activity, serological activity, duration, and
treatment. Within each of these domains a number of key issues were identified and these form the
basis of the work described here.
Preliminary statements on remission in SLE.
Ten statements, considered highly relevant for developing a definition of remission and expected to
be uncontroversial, were prepared by the steering committee and subjected to electronic voting by
the task force. Eight of these statements readily achieved a high level of consensus (>90%) and are
shown in table 1.
Statement % in favor
1 Remission is a desirable outcome for the patient with SLE 100%
2 Remission in SLE includes, at the very least, the absence of
symptoms and signs of SLE.
100%
3 Remission in SLE is not the same as a cure. 100%
4 Remission in SLE is not the same as low disease activity. 93%
5 Remission is a state that, if sustained, is associated with a low
likelihood of adverse outcome.
100%
6 “Serological activity” in SLE generally refers to the presence of 100%
9
anti-DNA antibodies and/or hypocomplementemia.
7 Treatment with antimalarials does not preclude the patient from
being considered to be in remission.
98%
8 Treatment with moderate- or high-dose steroids does preclude the
patient from being considered in remission.
98%
Table 1. Preliminary statements on remission in SLE. Out of ten statements selected by the steering
committee, eight achieved >90% agreement on electronic voting by the entire task force. Two
statements (“A definition of remission SLE must be reasonably consistent with the use of this term in
the literature” and “Durability in time can be added to any definition of remission in order to define a
‘durable remission’ but need not be included in the definition of remission itself”) did not achieve
consensus and were discussed further at the face-to-face meeting.
Therefore, remission is identified as a desirable outcome for patients with SLE with, -at the very
least-, the absence of major symptoms and signs of SLE. Remission is conceived of in terms
different from a cure, yet it is also regarded as meaningfully different from a low disease activity
state, including the lupus low disease activity state (LLDAS) that has recently been proposed by the
Asia-Pacific Lupus Collaboration.[5] Perhaps most critically for future work in this area, it is
recognized that remission, like LLDAS, has to be a state that, if sustained, is associated with a low
likelihood of adverse outcome. To this end, the systematic literature review identified a number of
observational studies in patients with lupus nephritis, which illustrate that attainment of (complete)
renal remission (or response) (typically defined as a very low level of proteinuria, with normal or
stable renal function, with or without inactive urine sediment) is associated with favorable long-term
patient and renal outcomes (Table 2). Similarly, in general SLE, three retrospective cohort studies
10
have suggested that patients who achieve disease remission have significantly lower rates of damage
accrual or mortality after follow-up.
11
Author
(ref.)
N Remission definition(s) Remission
achieved (%)
Association of remission with outcomes
General SLE
Drenkard
[6]
667 ≥1 year of clinically inactive disease (serological
activity allowed) that permitted withdrawal of all
lupus drugs
23.4% 12.5-fold reduced risk for death (follow-up 11.6 ± 6.0
years), after controlling for effects of renal disease
and thrombocytopenia
Nossent
[7]
200 Physician judgment (not otherwise specified),
assessed during the first year of disease
27.5% Lower annual relapse rates, lower average SLEDAI,
lower cumulative SDI scores at the end of 5-year
follow-up
Zen [8] 224 ≥5 years complete remission with SLEDAI-2K=0
(HCQ allowed) or clinical remission with clinical
SLEDAI-2K=0 (serological activity allowed) off-
steroids or on low-dose steroids (HCQ/ISTs
allowed)
7.1% (complete
remission),
14.7% (off-
steroids), 15.6%
(on steroids)
Damage accrual rates (end of 5-year follow-up):
18.8% (complete remission), 18.2% (off-steroids),
37.1% (on steroids), and 51.4% (no remission)
Medina-
Quiñones
[9]
532 ≥3 years with BILAG C, D or E, no serological
activity, off-steroids, off-immunosuppressives
(HCQ/NSAIDs allowed)
14.5% Lower mortality rates (5.2% vs. 13.4%; median
follow-up 12 years)
12
Lupus nephritis
Moroni
[10]
70 CRR: UPr* <0.2, normal renal function 38.5% (at last
follow-up)
CRR was associated with fewer renal flares, better
outcome of renal flares
Mok [11] 183 CRR: UPr <0.3, normal SAlb, normal renal
function, assessed at the end of first year of therapy
64% Lack of CRR was associated (RR 9.9) with
development of ESRD (mean follow-up 181 months)
Korbet
[12]
86 CRR: SCr ≤1.4 mg/dl, UPr ≤0.33, attained within 5
years of entering the study. See also refs [13], [14]
43% CRR was associated with reduced risk of progression
to ESRD (HR 0.12), increased rates of patient
survival at 5 and 10 years (follow-up 120 ± 65
months)
Illei [15] 145 CRR: SCr <130% of the lowest level during
treatment, UPr <1, inactive urine sediment, off IST
(HCQ and prednisone ≤10 mg/day allowed), for ≥6
months
50.3% Lack of CRR was associated with increased risk for
severe nephritic flare (LR 5.7) and progression to
ESRD (LR 7.0) (median follow-up 116 to 123
months)
Hill [16] 71 CRR: SCr ≤123 μmol/L, UPr ≤0.33 N/D Lack of CRR was associated with decreased 10-year
survival rates from doubling of SCr
Mok [17] 189 CRR: stabilized/improved SCr, UPr <1, improved 55% Lack of CRR was associated with increased risk (HR
13
serum C3 for ≥6 months, assessed at the end of IST 4.5) for development of ESRD (mean follow-up 96.5
months)
Mok [18] 268 Same as in [17] 59% Lack of CRR was associated with increased risk (HR
4.5) for adverse outcome (doubling of SCr or ESRD
or patient death)
Moroni
[19]
93 CRR: SCr <1.2 mg/dL, stable or 25% increase of
baseline CrCl, UPr <0.2, inactive urine sediment
82% (63.4% at
last follow-up)
Lack of CRR was associated (RR 4.3) with
development of chronic renal insufficiency (median
follow-up 181 months)
Mak [20] 149 CRR: stabilized/improved SCr, improved serum
complement, UPr <1, inactive urine sediment for ≥6
months, assessed at the end of first year of therapy
60.4% Lack of CRR was associated with renal damage
(mean follow-up 80 months)
Lee [21] 77 CRR: SCr <1.2 mg/dl, UPr <0.2, inactive urinary
sediment, for ≥6 months
52% Lack of CRR was associated with development of
chronic renal insufficiency and/or death (follow-up
8.3 ± 4.4 years)
Sun [22] 100 CRR: UPr ≤0.4, normal urinary sediment, normal
SAlb, normal SCr
58% Lack of CRR was associated with ESRD (median
follow-up 60 months)
Ayodele 105 CRR: stable [±25%] renal function, UPr <0.2, 44.8% CRR was associated with higher mean survival time
14
[23] assessed at the end of first year of therapy
So [24] 117 CRR: SCr ≤1.4 mg/dl, UPr ≤0.5, inactive urine
sediment, assessed after 6 months of therapy
50.4% CRR was associated with reduced risk for subsequent
renal flares and chronic renal failure (mean follow-up
66–76 months)
Reich [25] 98 CRR: SCr ≤120 mmol/l (1.4 mg/dl), UPr <0.3
74.5% Lack of CRR was associated with faster GFR decline
(follow-up 12.4 ± 8.4 years)
Alsuwaida
[26]
77 CRR: SCr ≤125 μmol/L, UPr ≤0.33 41.6% CRR was associated with higher renal survival rate at
10 years. Lower risk for doubling of SCr
Dhir [27] 188 UPr reduction by ≥50% to <2, inactive urine
sediment, normal SCr (≤1.5 mg/dl), assessed at the
end of first year
54.6% § Lack of remission was associated (HR 13.8) with
chronic renal failure or death (median follow-up 6
years)
Moroni
[28]
103 CRR: SCr <1.2 mg/dL, stable or 25% increase of
baseline CrCl, UPr <0.2, inactive urine sediment
70.9% CRR was associated with good renal outcome (no
chronic renal insufficiency) (follow-up 156 ± 105
months)
Mahmoud
[29]
135 CRR: SCr ≤1.2 mg/dl, and 25% increase of baseline
CrCl if abnormal, or stable value if abnormal at
59.3% Lack of CRR in the first year was associated with
adverse outcome (death, ESRD or doubling of SCr)
15
baseline, UPr <0.2, inactive urine sediment
Fernandes
das Neves
[30]
105 CRR: UPr <0.2, negative anti-dsDNA antibodies,
normal C3, and normal SCr, for ≥5 consecutive
years
38.1% CRR was associated with preservation of normal
renal function (80% vs. 43%) and reduced mortality
(0% vs. 22%) compared to partial/no remission group
(follow-up 13.7 ± 14.1 years)
Koo [31] 193 CRR: UPr <0.3, for ≥6 months 42.5% CRR was associated with reduced risk of mortality
and ESRD (follow-up 158 ± 70 months)
Dall’Era
[32]
76 Different sets of response criteria based on a range
of cut-offs of UPr, SCr, and RBCs at 3, 6, and 12
months. Best criterion was UPr <0.8 at 12 months
59.2% Sensitivity 81% and specificity 78% for favorable
long-term (7 years) renal outcome (SCr ≤1.0 mg/dl).
The LUNAR study remission criterion (UPr ≤0.5, SCr
±15% of baseline, inactive urine sediment) had 32%
sensitivity, 91% specificity
Tamirou
[33]
104 Different sets of CR criteria based on levels of UPr,
Scr, and urinary RBCs at 3, 6, and 12 months. Best
criterion was UPr ≤0.5 at 12 months
49.0% Positive predictive value 92% for achieving good
long-term renal outcome (SCr ≤120% of baseline
value) after median 110 months
Tamirou
[34]
80 Subgroup analysis of [33]. Different sets of
response criteria based on a range of cut-offs of
63.8% Sensitivity 71% and specificity 75% for favorable
long-term (7 years) renal outcome (SCr ≤1.0 mg/dl).
16
UPr, SCr, and RBCs at 3, 6, and 12 months. Best
criterion was UPr <0.7 at 12 months
Table 2. Validation of published definitions of disease remission against outcomes in SLE (studies with n ≥70 patients).
* Proteinuria (UPr) assessed by 24-hr urine collection and/or urine protein-to-creatinine ratio
§ n = 71 out of 130 with available records
Abbreviations: CRR, complete renal remission (or response); UPr, proteinuria; SCr, serum creatinine; GFR, glomerular filtration rate; CrCl,
creatinine clearance; RBCs, red blood cells; HR, hazard ratio; ESRD, end-stage renal disease; SDI, Systemic Lupus International Collaborating
Clinics/American College of Rheumatology (ACR) Damage Index SLICC group damage index; SAlb, serum albumin; IST, immunosuppressive
treatment; HCQ, hydroxychloroquine; N/D, not described.
17
Specific agreement was also achieved on the definition of “serological activity” where it was agreed
that there was sufficient support in the literature pertaining to the presence of anti-DNA antibodies
and/or hypocomplementemia (defined as above or below the upper limit of normal value for the local
laboratory, respectively), but without reference to other autoantibodies. The task force discussed
whether definitions of remission should distinguish patients who are serologically active from those
who are serologically inactive, as the former are much more likely to experience subsequent flare.[4,
9] No consensus was reached on that statement and the task force suggested to test each of the
clinical criteria with and without serology, in order to determine the usefulness of the latter and
whether it adds to the construct validity of each definition.
Finally, there was consensus in the task force that treatment with anti-malarials does not preclude the
patient from being considered to be in remission, even though it is somewhat paradoxical to say “off-
treatment” when someone is, in fact, taking a medication. However, this step was strongly supported
by the task force in respect of the widely-held view that anti-malarials are often considered long-term
maintenance therapy for patients with SLE even if they have achieved remission. Benefits of such
treatment are believed to extend beyond flare prevention and disease control, and it was therefore felt
incorrect to imply that these medication should be discontinued. The task force does recognize that
antimalarials have immunomodulatory effects, and that therefore studies done on patients in
remission “off treatment” (by the above definition) may in some instances have to distinguish clearly
between those patients who are and who are not taking antimalarials. This would perhaps seem most
important for studies of an immunological or pathophysiological nature. A similar arguments does of
course also apply to medications that do not fall in the above categories but that have or may have
immunomodulatory properties, such as statins and vitamin D.
It was also agreed upon by all that patients who are treated with moderate- or high-dose
glucocorticoids cannot be considered to be in remission, even if they would fulfill other criteria for
18
remission. The main argument for this is the well-established adverse health consequence of long-
term moderate- to high-dose glucocorticoid treatment.
Two statements were felt to be uncontroversial by the steering committee but did not achieve >90%
agreement in the larger task force. One of these, “A definition of remission in SLE must be
reasonably consistent with the use of this term in the literature” was intended by the steering
committee as indicating that a definition of remission must be aligned with what historically has
been considered to be a remission. However, this statement was felt to be a bit too circular by some,
given that the literature is divided on the definition of remission.
The statement “Durability in time can be added to any definition of remission in order to define a
‘durable remission’ – but need not be included in the definition of remission itself.” achieved 86%
agreement by pre-meeting electronic voting. Notably, although a few of the published definitions
included in Table 2 have incorporated a “duration” component (ranging from 6 months to 5 years),
the majority to the studies has not examined the prognostic importance of duration of remission
against long-term patient outcomes. When discussed face-to-face by the full task force, an increasing
number of delegates were unable to support this statement. After discussion, the vote was 65% in
favor – not sufficient to declare consensus. The main arguments for and against this statement, as
they were discussed during the meeting, are given in Table 3:
In favor of the original statement
(i.e, the definition of remission does not
have to include the duration)
Against the original statement
(i.e., the definition of remission does have to
include the duration)
Definitions of remission in other
autoimmune diseases, including
As SLE can be remitting-relapsing,[37]
for a patient to be in remission at one
19
rheumatoid arthritis [35] and Crohn’s
disease,[36] do not include durability
specific point in time may not be
clinically relevant
Including durability in the definition
itself would severely limit the use of the
definition as an outcome in clinical trials
Remission for only a short period of time
has little relevance in SLE
Duration can always be added to the
analyses in which the definition is used
Table 3. Arguments for and against the statement “Durability in time can be added to any definition
of remission in order to define a ‘durable remission’ but need not be included in the definition of
remission itself.”
The framework for a definition.
The task force discussed what form a definition of remission in SLE should take. A literature search
on this topic identified many observational studies and clinical trials that used a large number of
different ad hoc definitions of remission in general SLE (Appendix Table 1) and in lupus nephritis
(Appendix Table 2). After extensively reviewing various options, and with particular attention to the
discussion described above regarding duration, the following three key principles were agreed upon
(summarized in Table 4):
Key principles for defining remission in SLE Agreement
1. Definitions of remission in SLE will be worded as follows: Remission 93%
20
in SLE is a durable state characterized by ………………….
(reference to symptoms, signs, routine labs)
o Requirement for serology may be added
(2 abstained)
2. For defining remission in SLE, a validated index must be used
o Suggested indices are: clinical SLEDAI = 0; BILAG 2004 D
or E only; clinical ECLAM = 0
o These must be supplemented by the Physician’s Global
Assessment being below an appropriate threshold (e.g., <0.5
on a 0–3 scale)
98%
3. A distinction will be made between remission off therapy and
remission on therapy
o Remission off therapy requires the patient to be on no other
treatment for SLE than maintenance antimalarials
o Remission on therapy allows patients to be treated with
maintenance antimalarials, stable, low-dose glucocorticoids
(e.g., prednisone <5 mg/day), maintenance
immunosuppressives and/or stable (maintenance) biologics
100%
(3 abstained)
Table 4. The task force’s three key recommendations for defining remission in SLE.
1. The task force achieved consensus (93%) for the principle that remission in SLE will be defined
using the following format:
21
“Remission in SLE is a durable state characterized by …. (followed by a reference indicating the
absence of symptoms, signs or abnormal labs)”.
It can be recognized that this definition is to some extent a compromise because it does not
specify the length of time during which a remission would have to be sustained in order to
qualify. This is a direct result of the fact that no agreement on this could be achieved and that the
task force felt that further scientific studies are needed to define the optimal duration for any
statement of remission in SLE. A further area of uncertainty was whether the absence of active
serology would be required and yet again it was felt that this could be investigated in the future.
It should therefore also be recognized that ‘abnormal labs’ in the above statement refers to
routine laboratory assessments and not necessarily to anti-DNA antibodies or complement levels.
2. The task force spent much time on finding correct formulations for defining the absence of
clinical signs and symptoms for use in a definition and agreed, in the end, that for this a validated
index must be used (98% agreement). The task force specifically suggests that the following can
be considered: clinical SLEDAI = 0; BILAG 2004 D or E categories only; or clinical ECLAM =
0. Furthermore, it is recommended that each of these indices is supplemented with the
requirement for the Physician’s Global Assessment (PhGA) to be below a certain level: in the
case of a PhGA ranging from 0 to 3 that should be < 0.5. Note that in all instances the term
“clinical” for SLEDAI and ECLAM refers to symptoms, signs and routine laboratory testing and
disregarding only the points that can be given for the presence of anti-DNA antibodies and/or
low complement. The task force also discussed the possibility of defining remission in terms of
specific symptoms and signs, such as was done for the proposed definition of remission in
pediatric SLE, where certain symptoms and signs are “allowed” for patients with SLE who are
nevertheless considered to be in remission.[38] Although a minority of participants favored this
22
approach, there was a more widespread feeling that not using validated indices would to some
extent be retrograde, and that practice in various research settings would also increasingly be
dominated by the use of such indices.
3. The task force recommends that a distinction should be made between “remission off therapy”
and “remission on therapy” (100% agreement). These two descriptors were chosen in preference
to many other suggested terms, some of which are: “complete” versus “partial” remission;
“complete” versus “clinical” remission; “remission” versus “lupus under control” or “inactive
disease”. While there are subtle nuances differentiating between these possibilities, it was
considered important to simplify this matter and to strictly limit the number of definitions to two
levels of remission.
In this regard, it is also important that “off-therapy” will mean that the patient is on no other
immunomodulatory treatment for SLE than possibly anti-malarials. As pointed out earlier, for
some studies, in particular mechanistic investigations, the immunomodulatory properties of
antimalarials must be considered, and in general accurate recording of all medications is
recommended.
“Remission-on-therapy” will allow some, but not all medications. Specifically, stable
immunosuppressives, including biological immunomodulators, are allowed within this level of
remission. It was noted that definitions of remission in other autoimmune diseases, including
rheumatoid arthritis[35] and Crohn’s disease[36], do not exclude the chronic use of specific
antirheumatic medications, immunosuppressives, or biologics. Likewise, these definitions do not
limit the use of glucocorticoids. However, in SLE a major contributor to long-term damage and
other adverse outcomes is the chronic use of glucocorticoids, and the task force felt that for the
patient to be declared in “remission-on-treatment” the highest allowable dose of glucocorticoids
23
is 5 mg/day prednisone (or equivalent). Prednisone dose thresholds associated with protection
from treatment-related harm are currently being studied by several groups and data from those
studies should further inform the selection of a threshold glucocorticoid dose in a definition of
remission-on-therapy.
Further development of the most appropriate definition of remission. The task force discussed in
what manner a future definition of remission in SLE could be most thoroughly established.
It was agreed upon by voting that for testing the construct validity of each potential remission
definition the most appropriate outcomes are death, damage, lupus flares, and HR-QOL measures
(100% agreement).
Thus, the task force indicated that any definition of remission in SLE must be tested in terms of the
degree to which it correctly identifies patients whose future disease course will be better in these four
outcomes. Though mortality remains a key outcome, it is unlikely that many studies will be able to
identify this as a differentiating factor. Damage as measured by the SLICC damage index (SDI) [39]
will most likely be the most effective way of ascertaining the construct validity of a definition of
remission, as has been provisionally demonstrated for the definition of LLDAS. However, the
occurrence of flares, especially severe flares, that can be measured by a variety of instruments,[40-
42] and measures of HR-QoL will also be important in determining which potential definition of
remission in SLE has the greatest validity.
Other points of discussion.
Patient’s Global Assessment. There was controversy about the role of the Patient’s Global
Assessment (PGA) in a remission definition. A majority felt that PGA cannot currently be included
24
pending further research, and specifically that such research is needed to validate PGA as an
outcome in reference to remission. Many felt that a better instrument to capture the patient’s
perspective may be needed. However, patient representatives (authors KL, CC, BvL) were concerned
that the patient perspective was omitted. Indeed, in the T2T recommendations for SLE, both
overarching principles and specific recommendations advocate including the patient’s perspective in
decision-making. However, there is no fully validated measure for the patient’s perspective at this
time. It was remarked that the PhGA can reflect patient perspective, and it was proposed to
emphasize that PhGA should pay careful attention to patient symptoms, or conversely, that PGA
could be a longer-term outcome used in the testing of remission definitions; but in formal votes no
consensus was reached on these points.
Inclusion of validated skin score. The dermatologists in the task force (authors AK and VPW)
suggested to supplement the definition of remission with a validated skin score.
Definition based only on symptoms. A rheumatologist (author MW) pointed out that in as much as
the task force is developing possible definitions of remission, a definition based only on symptoms
and without the use of an index could also be tested.
Plans for further work and research agenda. The task force agreed upon a plan of work that would
include the use of longitudinal datasets from clinical trials, observational studies, registries etc. to
test each of the definitions of remission. Likewise, definitions of remission “on treatment” and “off
treatment” will be tested separately against the pre-specified dependent outcomes indicated above,
and different durations of these definitions will also be tested. Moreover, studies done on patients
“off treatment” will also record the use of antimalarials and analyze the extent to which this makes a
difference. As always, findings in such subanalyses may inform future changes in the proposed
definitions.
Proposed durations to be analyzed include 6 months, 12 months, 2 years, and 5 years.
25
In addition to this continued work, the task force also recommends specific research to investigate
whether definitions of remission are applicable irrespective of genetic backgrounds and/or ethnicity.
Discussion
An international task force consisting of patient representatives and specialists in clinical
immunology, dermatology, nephrology and rheumatology was convened and achieved high-level
agreement on eight statements, three key principles, and a set of outcomes relating to remission in
SLE, thereby providing a road-map for further work towards a generally applicable definition.
Remission was approached as a global state, whereas it is recognized that remission can be defined,
and has in some instances been defined, at the individual organ system level.
As a conceptual starting-point remission was identified as a desirable outcome for patients with SLE
with at the very least the absence of major symptoms and signs of SLE. Remission is considered
distinct from a cure and it is also regarded as meaningfully different from a state of low disease
activity in SLE such as the lupus low disease activity state (LLDAS) that has recently been
developed by the Asia-Pacific Lupus Collaboration.[5] However, the latter definition does not solely
require the presence of low disease activity and does therefore, in fact, include both patients who
have a low level of disease activity and also those who are in remission.
Perhaps most critically for future work in this area, it is recognized that remission has to be a state
that, if sustained, is associated with a low likelihood of adverse outcome.
Regarding treatment, there was consensus that treatment with antimalarials does not preclude the
patient from being considered to be in remission, in respect of the recommendation that anti-
malarials should be considered as long-term maintenance therapy for patients with SLE even if they
26
have achieved remission.[3] It was also agreed upon by all that patients who are treated with
moderate- or high-dose glucocorticoids cannot be considered to be in remission even if they would
fulfill other criteria for remission. It is well established that glucocorticoids may suppress signs of
disease, but will not achieve bona fide disease control, and also constitute one of the major risk
factors for negative outcomes in SLE.
In contrast to these areas of agreement, no consensus could be achieved on two important issues.
First, it transpired that the inclusion of ‘duration’ in a definition of remission was controversial.
Some argued that definitions of remission in other disease areas do not have this requirement, and
that utility of a definition in clinical studies including clinical trials will be significantly limited if
duration is explicitly required. Others argued that remission achieved on only one given point in time
lacks clinical relevance in a disease that can be relapsing and remitting. Following lengthy
discussion, the task force was able to agree on a compromise using the wording “Remission is a
durable state characterized by ....” and also clearly identified the need for studies linking the duration
of any definition of remission with longer-term outcomes.
Second, the task force did not agree on the precise role of the Patient Global Assessment (Patient
GA) in a remission definition. This issue was debated at considerable length. Several task force
members including patient representatives were concerned that the patient perspective was not
explicitly included in the definition, and emphasized the importance of a definition of remission that
‘resonates’ with the patient. However, a majority of the task force felt that while the patient’s
perspective is critically important in the patient-physician interaction, when it comes to a definition
of remission for the purposes of clinical and epidemiological studies and clinical trials more work is
needed in order either to validate Patient GA as an outcome,or more likely to develop a better
instrument to capture the patient’s perspective. It was pointed out that the physician, when assessing
disease activity, is expected to weigh in the patient’s perspective.
27
Additionally, the task force agreed on the definition of “serological activity” but no consensus was
reached regarding whether the latter should be taken into account to define remission. The task force
agreed upon the use of longitudinal datasets to determine whether serology adds to the construct
validity of each definition.
Nomenclature for remission in SLE was extensively discussed. Many terms were proposed,
including “complete remission”, “partial” remission”, “clinical remission”, “serological remission”,
“lupus under control”, “inactive disease” etc., many of which were overlapping. In order to simplify
matters and achieve consistency the task force recommends that only one distinction is made
between “remission off therapy” and “remission on therapy”, where “off-therapy” must mean that
the patient is on no systemic treatments for SLE other than anti-malarials. While “remission-on-
antimalarials-only” would be the most accurate term for this state, “remission off-therapy” was
chosen for brevity and convenience, even though it does allow antimalarial therapy. As stated
previously, it will be necessary in future studies to account for the actual use of antimalarials in this
group of patients, and subsequent analyses of patients who are and who are not on antimalarials may
lead to further distinctions in these categories.
“Remission-on-therapy” will allow stable immunosuppressives, including biologics, and low-dose
glucocorticoids. It is of interest to note that the latter type of definition is the more usual in other
autoimmune diseases, such as RA and Crohn’s disease, and would also allow investigators to use the
definition in clinical trials.
One limitation of the approach taken by the task force is the decision to limit serological activity to
anti-DNA antibodies and low complement. Recent research shows the importance of antibodies to
RNA binding proteins (RBPs) to the formation of immune complexes that can stimulate interferon
production. Further research may show that, unless these antibodies are assayed, the serological
assessment is incomplete.
28
Finally, the task force recommends a clear research agenda of testing the construct validity of
potential remission definitions against death, damage, lupus flares, and HR-QOL measures as
outcomes (dependent variables) in suitable cohorts of patients. Several task force members have
conducted or are conducting such studies. This approach will establish which definition(s) of
remission in SLE optimally identifies patients with a better disease course in these four outcomes.
In summary, a set of statements and key principles relevant to remission in SLE were
established by an international task force. This work provides a pathway for testing individual
definitions against longer-term outcomes in order to arrive at a definition of remission in SLE.
29
Acknowledgments
The authors wish to acknowledge Ms Lisbeth Löfstrand, Administrator at Karolinska Institutet for
her invaluable help during the organization of the DORIS meetings as well as for manuscript
preparation.
Competing Interests
Ronald van Vollenhoven reports having received Research Support and Grants from AbbVie,
Amgen, BMS, GSK, Pfizer, Roche, UCB, and Consultancy or honoraria from AbbVie, Biotest,
BMS, Celgene, Crescendo, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, Vertex.
Laurent Arnaud reports having received travel grants, consultancy or honoraria from
Adelphivalues, Amgen, Eli Lilly, GSK, LFB, Menarini France, MSD, Raison de santé.
Funding
No funding declared
30
References
1 Houssiau FA, Vasconcelos C, D'Cruz D, et al. The 10-year follow-up data of the Euro-Lupus Nephritis
Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis 2010;1:61-4.
2 Bexelius C, Wachtmeister K, Skare P, et al. Drivers of cost and health-related quality of life in patients
with systemic lupus erythematosus (SLE): a Swedish nationwide study based on patient reports. Lupus
2013;8:793-801.
3 van Vollenhoven RF, Mosca M, Bertsias G, et al. Treat-to-target in systemic lupus erythematosus:
recommendations from an international task force. Ann Rheum Dis 2014;6:958-67.
4 Steiman AJ, Urowitz MB, Ibanez D, et al. Prolonged clinical remission in patients with systemic lupus
erythematosus. J Rheumatol 2014;9:1808-16.
5 Franklyn K, Lau CS, Navarra SV, et al. Definition and initial validation of a Lupus Low Disease Activity
State (LLDAS). Ann Rheum Dis 2015.
6 Drenkard C, Villa AR, Garcia-Padilla C, et al. Remission of systematic lupus erythematosus. Medicine
(Baltimore) 1996;2:88-98.
7 Nossent J, Kiss E, Rozman B, et al. Disease activity and damage accrual during the early disease course
in a multinational inception cohort of patients with systemic lupus erythematosus. Lupus 2010;8:949-56.
8 Zen M, Iaccarino L, Gatto M, et al. Prolonged remission in Caucasian patients with SLE: prevalence and
outcomes. Ann Rheum Dis 2015;12:2117-22.
43 Medina-Quinones CV, Ramos-Merino L, Ruiz-Sada P, et al. Analysis of Complete Remission in Lupus
Patients over a period of 32 years. Arthritis care & research 2015.
9 Moroni G, Quaglini S, Maccario M, et al. "Nephritic flares" are predictors of bad long-term renal
outcome in lupus nephritis. Kidney Int 1996;6:2047-53.
10 Mok CC, Wong RW and Lau CS. Lupus nephritis in Southern Chinese patients: clinicopathologic
findings and long-term outcome. Am J Kidney Dis 1999;2:315-23.
11 Korbet SM, Lewis EJ, Schwartz MM, et al. Factors predictive of outcome in severe lupus nephritis.
Lupus Nephritis Collaborative Study Group. Am J Kidney Dis 2000;5:904-14.
31
12 Najafi CC, Korbet SM, Lewis EJ, et al. Significance of histologic patterns of glomerular injury upon
long-term prognosis in severe lupus glomerulonephritis. Kidney Int 2001;6:2156-63.
13 Chen YE, Korbet SM, Katz RS, et al. Value of a complete or partial remission in severe lupus nephritis.
Clin J Am Soc Nephrol 2008;1:46-53.
14 Illei GG, Takada K, Parkin D, et al. Renal flares are common in patients with severe proliferative lupus
nephritis treated with pulse immunosuppressive therapy: long-term followup of a cohort of 145 patients
participating in randomized controlled studies. Arthritis Rheum 2002;4:995-1002.
15 Hill GS, Delahousse M, Nochy D, et al. Outcome of relapse in lupus nephritis: roles of reversal of renal
fibrosis and response of inflammation to therapy. Kidney Int 2002;6:2176-86.
16 Mok CC, Ying KY, Tang S, et al. Predictors and outcome of renal flares after successful
cyclophosphamide treatment for diffuse proliferative lupus glomerulonephritis. Arthritis Rheum 2004;8:2559-
68.
17 Mok CC, Ying KY, Ng WL, et al. Long-term outcome of diffuse proliferative lupus glomerulonephritis
treated with cyclophosphamide. Am J Med 2006;4:355 e25-33.
18 Moroni G, Quaglini S, Gallelli B, et al. The long-term outcome of 93 patients with proliferative lupus
nephritis. Nephrol Dial Transplant 2007;9:2531-9.
19 Mak A, Mok CC, Chu WP, et al. Renal damage in systemic lupus erythematosus: a comparative analysis
of different age groups. Lupus 2007;1:28-34.
20 Lee BS, Cho HY, Kim EJ, et al. Clinical outcomes of childhood lupus nephritis: a single center's
experience. Pediatr Nephrol 2007;2:222-31.
21 Sun HO, Hu WX, Xie HL, et al. Long-term outcome of Chinese patients with membranous lupus
nephropathy. Lupus 2008;1:56-61.
22 Ayodele OE, Okpechi IG and Swanepoel CR. Predictors of poor renal outcome in patients with biopsy-
proven lupus nephritis. Nephrology (Carlton) 2010;4:482-90.
23 So MW, Koo BS, Kim YG, et al. Predictive value of remission status after 6 months induction therapy in
patients with proliferative lupus nephritis: a retrospective analysis. Clin Rheumatol 2011;11:1399-405.
24 Reich HN, Gladman DD, Urowitz MB, et al. Persistent proteinuria and dyslipidemia increase the risk of
progressive chronic kidney disease in lupus erythematosus. Kidney Int 2011;8:914-20.
32
25 Alsuwaida A, Husain S, Alghonaim M, et al. Strategy for second kidney biopsy in patients with lupus
nephritis. Nephrol Dial Transplant 2012;4:1472-8.
26 Dhir V, Aggarwal A, Lawrence A, et al. Long-term outcome of lupus nephritis in Asian Indians. Arthritis
Care Res (Hoboken) 2012;5:713-20.
27 Moroni G, Quaglini S, Gravellone L, et al. Membranous nephropathy in systemic lupus erythematosus:
long-term outcome and prognostic factors of 103 patients. Semin Arthritis Rheum 2012;5:642-51.
28 Mahmoud GA, Zayed HS and Ghoniem SA. Renal outcomes among Egyptian lupus nephritis patients: a
retrospective analysis of 135 cases from a single centre. Lupus 2015;3:331-8.
42 Fernandes das Neves M, Irlapati RV and Isenberg D. Assessment of long-term remission in lupus
nephritis patients: a retrospective analysis over 30 years. Rheumatology (Oxford) 2015;8:1403-7.
29 Koo HS, Kim S and Chin HJ. Remission of proteinuria indicates good prognosis in patients with diffuse
proliferative lupus nephritis. Lupus 2016;1:3-11.
30 Dall'Era M, Cisternas MG, Smilek DE, et al. Predictors of long-term renal outcome in lupus nephritis
trials: lessons learned from the Euro-Lupus Nephritis cohort. Arthritis Rheumatol 2015;5:1305-13.
31 Tamirou F, D'Cruz D, Sangle S, et al. Long-term follow-up of the MAINTAIN Nephritis Trial, comparing
azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis. Ann Rheum Dis 2015.
32 Tamirou F, Lauwerys BR, Dall'Era M, et al. A proteinuria cut-off level of 0.7 g/day after 12 months of
treatment best predicts long-term renal outcome in lupus nephritis: data from the MAINTAIN Nephritis Trial.
Lupus Sci Med 2015;1:e000123.
33 Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League against
Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis
2011;3:404-13.
34 Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn's disease activity index. National
Cooperative Crohn's Disease Study. Gastroenterology 1976;3:439-44.
35 Barr SG, Zonana-Nacach A, Magder LS, et al. Patterns of disease activity in systemic lupus
erythematosus. Arthritis Rheum 1999;12:2682-8.
36 Mina R, Klein-Gitelman MS, Ravelli A, et al. Inactive disease and remission in childhood-onset systemic
lupus erythematosus. Arthritis care & research 2012;5:683-93.
33
37 Gladman D, Ginzler E, Goldsmith C, et al. The development and initial validation of the Systemic Lupus
International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus
erythematosus. Arthritis and rheumatism 1996;3:363-9.
38 Gordon C, Sutcliffe N, Skan J, et al. Definition and treatment of lupus flares measured by the BILAG
index. Rheumatology (Oxford) 2003;11:1372-9.
39 Merrill J, Buyon J, Furie R, et al. Assessment of flares in lupus patients enrolled in a phase II/III study of
rituximab (EXPLORER). Lupus 2011;7:709-16.
40 Isenberg DA, Allen E, Farewell V, et al. An assessment of disease flare in patients with systemic lupus
erythematosus: a comparison of BILAG 2004 and the flare version of SELENA. Ann Rheum Dis 2011;1:54-9.
